PROJECT SUMMARY/ABSTRACT Tooth enamel is formed by ameloblasts in two main stages, secretory and maturation, with cells of each stage being functionally distinct. The volume (thickness) of enamel is formed in the secretory stage and then mineralized in the maturation stage by increased ion transport. Dysregulation of the processes that define either stage leads to dental disease. Enamel formation has been studied most commonly by analyzing the role of enamel matrix proteins and proteases. Methodological advances, some developed in the PI's lab, and the ongoing integration of enamel biology with other disciplines, provide a platform to address key aspects of the physiology and metabolism of enamel cells in enamel mineralization and dental disease. This grant proposal will identify novel molecular pathways in enamel formation by linking Ca2+ homeostasis with the redox environment and mitochondrial function. To do this, we will use, among other systems, mouse models lacking Ca2+ influx and mice lacking mitochondrial Ca2+ uptake. The role/s of mitochondria and redox in signaling and metabolism during enamel formation are presently unknown.